EP3173413B1 - Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme - Google Patents
Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme Download PDFInfo
- Publication number
- EP3173413B1 EP3173413B1 EP16205139.5A EP16205139A EP3173413B1 EP 3173413 B1 EP3173413 B1 EP 3173413B1 EP 16205139 A EP16205139 A EP 16205139A EP 3173413 B1 EP3173413 B1 EP 3173413B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pyrimidin
- pyrazolo
- dihydroxy
- cyclopentyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 230000005382 ubiquitin homeostasis Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to a chemical entity chosen from:
- C 1-6 alkyl groups include the aforementioned C 1-4 alkyl groups as well as pentyl, isopentyl, neopentyl, hexyl and the like. Additional examples of alkyl groups include heptyl, octyl and the like.
- C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl, pentadienyl, hexenyl and the like. Additional examples of alkenyl include heptenyl, octenyl, octatrienyl and the like.
- aliphatic refers to alkyl, alkenyl and alkynyl groups as defined above.
- C 1-6 aliphatic it can be substituted with C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl.
- perhaloalkoxy groups include the aforementioned perfluoroalkoxy groups as well as -OCCl 3 , -OCFCl 2 , -OCF 2 Cl, CCl 2 CCl 3 and the like.
- haloalkoxy groups include the aforementioned perhaloalkoxy groups as well as -OCH 2 F, -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH(Cl)CH 2 Br, -OCH 2 CH(F)CH 2 Cl and the like.
- carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms. In some embodiments (“C 3-8 carbocyclyl”), a carbocyclyl group has from 3 to 8 ring carbon atoms. In some embodiments (“C 3-6 carbocyclyl”), a carbocyclyl group has from 3 to 6 ring carbon atoms.
- the chemical entities of this invention are useful inhibitors of UAE activity.
- Inhibitors are meant to include chemical entities which reduce the promoting effects of UAE initiated conjugation of ubiquitin to target proteins (e.g., reduction of ubiquitination), reduce intracellular signaling mediated by ubiquitin conjugation, and/or reduce proteolysis mediated by ubiquitin conjugation (e.g., inhibition of cellular ubiquitin conjugation, ubiquitin dependent signaling and ubiquitin dependent proteolysis (e.g., the ubiquitin-proteasome pathway)).
- the chemical entities of this invention may be assayed for their ability to inhibit UAE in vitro or in vivo, or in cells or animal models according to methods provided in further detail herein, or methods known in the art.
- LCMS data were obtained either (i) using an Agilant 1100 LC (column: Waters Symmetry, 3.5 ⁇ m C18 100 ⁇ 4.6 mm) and a Waters ZQ MS using the following gradients:
- Step 3 2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid
- Step 2 (s.e.)-[(3aR,4R,6R,6aS)-6- ⁇ [2-(4-chloro-1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino ⁇ -2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol
- composition of the formulation of (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)cyclopentyl)methyl sulfamate for injection is shown in Table 6
- Table 6 Quantitative composition of sterile solution for parenteral administration Component Function Amount (mg/mL) Citric Acid anhydrous, USP Excipient 9.61 ⁇ -Cyclodextrin Sulfobutyl Ethers, Sodium Salts (Captisol®) (Ligand Pharmaceuticals Inc)
- Excipient 50 (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(3-(trifluoromethylthio)phenyl)pyrazolo[1,5-a]pyrimidin-7-yla
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP19170607.6A EP3536692B1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261600070P | 2012-02-17 | 2012-02-17 | |
| PCT/US2013/026113 WO2013123169A1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| EP13748707.0A EP2814791A4 (en) | 2012-02-17 | 2013-02-14 | PYRAZOLOPYRIMIDINYL INHIBITORS OF ACTIVATION ENZYME OF UBIQUITIN |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP13748707.0A Division EP2814791A4 (en) | 2012-02-17 | 2013-02-14 | PYRAZOLOPYRIMIDINYL INHIBITORS OF ACTIVATION ENZYME OF UBIQUITIN |
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| EP19170607.6A Division EP3536692B1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
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| EP3173413A1 EP3173413A1 (en) | 2017-05-31 |
| EP3173413B1 true EP3173413B1 (en) | 2019-05-01 |
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| EP16205139.5A Active EP3173413B1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| EP19170607.6A Active EP3536692B1 (en) | 2012-02-17 | 2013-02-14 | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| EP13748707.0A Withdrawn EP2814791A4 (en) | 2012-02-17 | 2013-02-14 | PYRAZOLOPYRIMIDINYL INHIBITORS OF ACTIVATION ENZYME OF UBIQUITIN |
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| EP13748707.0A Withdrawn EP2814791A4 (en) | 2012-02-17 | 2013-02-14 | PYRAZOLOPYRIMIDINYL INHIBITORS OF ACTIVATION ENZYME OF UBIQUITIN |
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| Country | Link |
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| EP (3) | EP3173413B1 (zh) |
| JP (1) | JP6122877B2 (zh) |
| KR (1) | KR20140123104A (zh) |
| CN (1) | CN104136399B (zh) |
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| CR (1) | CR20140380A (zh) |
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| ES (1) | ES2739150T3 (zh) |
| GE (1) | GEP201706687B (zh) |
| HK (1) | HK1201817A1 (zh) |
| IL (1) | IL234016A0 (zh) |
| MA (1) | MA35932B1 (zh) |
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| NZ (1) | NZ628969A (zh) |
| PE (1) | PE20142244A1 (zh) |
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| SG (2) | SG11201404757WA (zh) |
| TN (1) | TN2014000351A1 (zh) |
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| US8008307B2 (en) | 2006-08-08 | 2011-08-30 | Millennium Pharmaceuticals, Inc. | Heteroaryl compounds useful as inhibitors of E1 activating enzymes |
| US9290500B2 (en) | 2012-02-17 | 2016-03-22 | Millennium Pharmaceuticals, Inc. | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| WO2014022744A1 (en) | 2012-08-03 | 2014-02-06 | Millennium Pharmaceuticals, Inc. | INDOLE-SUBSTITUTED PYRROLOPYRIMIDINYL INHIBITORS OF Uba6 |
| EA032577B1 (ru) | 2013-07-02 | 2019-06-28 | Милленниум Фармасьютикалз, Инк. | Гетероарильные соединения, пригодные в качестве ингибиторов sumo-активирующего фермента |
| UA122963C2 (uk) | 2014-07-01 | 2021-01-27 | Мілленніум Фармасьютікалз, Інк. | Гетероарильні сполуки, придатні як інгібітори sumo-активуючого ферменту |
| JP6697453B2 (ja) | 2014-10-29 | 2020-05-20 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | ユビキチン活性化酵素阻害物質及び放射線の投与 |
| JP6698648B2 (ja) | 2014-10-29 | 2020-05-27 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | ユビキチン活性化酵素阻害物質及び化学療法剤の投与 |
| MA54092A (fr) | 2018-10-30 | 2021-09-08 | Kronos Bio Inc | Composés, compositions et procédés de modulation de l'activité de cdk9 |
| WO2023021498A1 (en) * | 2021-08-16 | 2023-02-23 | Moya Bio Ltd. | Fused azole and furan based nucleoside analogs and uses thereof |
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| MY145332A (en) | 2002-09-04 | 2012-01-31 | Schering Corp | Trisubstituted 4-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors |
| US7196092B2 (en) | 2002-09-04 | 2007-03-27 | Schering Corporation | N-heteroaryl pyrazolopyrimidines as cyclin dependent kinase inhibitors |
| US7078525B2 (en) | 2002-09-04 | 2006-07-18 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
| US7563798B2 (en) | 2002-09-04 | 2009-07-21 | Schering Corporation | Substituted pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors |
| WO2004087707A1 (en) | 2003-03-31 | 2004-10-14 | Vernalis (Cambridge) Limited | Pyrazolopyrimidine compounds and their use in medicine |
| JP2005008581A (ja) * | 2003-06-20 | 2005-01-13 | Kissei Pharmaceut Co Ltd | 新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途 |
| EP1680431A1 (en) | 2003-10-17 | 2006-07-19 | Rigel Pharmaceuticals, Inc. | Benzothiazole and thiazole'5,5-b!pyridine compositions and their use as ubiquitin ligase inhibitors |
| US20050282818A1 (en) | 2004-06-22 | 2005-12-22 | Rigel Pharmaceuticals, Inc. | Ubiquitin ligase inhibitors |
| SI1848718T1 (sl) | 2005-02-04 | 2012-12-31 | Millennium Pharmaceuticals, Inc. | Inhibitorji E1 aktivacijskih enzimov |
| TWI333953B (en) | 2005-10-06 | 2010-12-01 | Schering Corp | Pyrazolopyrimidines as protein kinase inhibitors |
| EP1989206B1 (en) | 2006-02-02 | 2012-07-04 | Millennium Pharmaceuticals, Inc. | Inhibitors of e1 activating enzyme |
| CN101395698B (zh) * | 2006-02-28 | 2010-06-09 | 兰姆研究股份公司 | 用于液体处理盘形物体的装置及方法 |
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| US9216983B2 (en) | 2007-12-21 | 2015-12-22 | Board Of Regents, University Of Texas System | Dihydroorotate dehydrogenase inhibitors with selective anti-malarial activity |
| WO2010086040A1 (en) | 2009-01-29 | 2010-08-05 | Biomarin Iga, Ltd. | Pyrazolo-pyrimidines for treatment of duchenne muscular dystrophy |
| WO2010088518A2 (en) | 2009-01-31 | 2010-08-05 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
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| AU2010347233B2 (en) | 2010-03-01 | 2015-06-18 | Oncternal Therapeutics, Inc. | Compounds for treatment of cancer |
| US20120077814A1 (en) | 2010-09-10 | 2012-03-29 | Zhong Wang | Sulfonamide, sulfamate, and sulfamothioate derivatives |
| CN103889988B (zh) | 2011-08-24 | 2018-05-04 | 米伦纽姆医药公司 | Nedd8-活化酶的抑制剂 |
| US9290500B2 (en) | 2012-02-17 | 2016-03-22 | Millennium Pharmaceuticals, Inc. | Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme |
| WO2014022744A1 (en) | 2012-08-03 | 2014-02-06 | Millennium Pharmaceuticals, Inc. | INDOLE-SUBSTITUTED PYRROLOPYRIMIDINYL INHIBITORS OF Uba6 |
| EA032577B1 (ru) | 2013-07-02 | 2019-06-28 | Милленниум Фармасьютикалз, Инк. | Гетероарильные соединения, пригодные в качестве ингибиторов sumo-активирующего фермента |
| UA122963C2 (uk) | 2014-07-01 | 2021-01-27 | Мілленніум Фармасьютікалз, Інк. | Гетероарильні сполуки, придатні як інгібітори sumo-активуючого ферменту |
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